Sequence analysis of the coding regions and splice site sequences in inherited retinal diseases is not able to uncover ∼40% of the causal variants. Whole-genome sequencing can identify most of the non-coding variants, but their interpretation is still very challenging, in particular when the relevant gene is expressed in a tissue-specific manner. Deep-intronic variants in ABCA4 have been associated with autosomal-recessive Stargardt disease (STGD1), but the exact pathogenic mechanism is unknown. By generating photoreceptor precursor cells (PPCs) from fibroblasts obtained from individuals with STGD1, we demonstrated that two neighboring deep-intronic ABCA4 variants (c...

Chronic degeneration of the Retinal Pigment Epithelium (RPE) is a precursor to pathological changes in the outer retina. The RPE monolayer, which lies beneath the neuroretina, daily internalises and digests large volumes of spent photoreceptor outer segments. Impaired cargo handling and processing in the endocytic/phagosome and autophagy pathways lead to the accumulation of lipofuscin and pyridinium bis-retinoid A2E aggregates and chemically modified compounds such as malondialdehyde and 4-hydroxynonenal within RPE...

PURPOSE: Inherited retinal dystrophies (IRDs) represent a group of progressive conditions affecting the retina. There is a great genetic heterogeneity causing IRDs, and to date, more than 260 genes are associated with IRDs. Stargardt disease, type 1 (STGD1) or macular degeneration with flecks, STGD1 represents a disease with early onset, central visual impairment, frequent appearance of yellowish flecks and mutations in the ATP-binding cassette subfamily A, member 4 (ABCA4) gene. A large number of intronic sequence variants in ABCA4 have been considered pathogenic although their functional effect was seldom demonstrated...

Purpose: To describe the retinal clinical features of a group of Mexican patients with Stargardt disease carrying the uncommon p.Ala1773Val founder mutation in ABCA4. Methods: Ten patients carrying the p.Ala1773Val mutation, nine of them homozygously, were included. Visual function studies included best-corrected visual acuity, electroretinography, Goldmann kinetic visual fields, and full-field electroretinography (ERG). In addition, imaging studies, such as optical coherence tomography (OCT), short-wave autofluorescence imaging, and quantitative analyses of hypofluorescence, were performed in each patient...

Purpose: Stargardt disease (STGD) is the most common form of inherited juvenile macular degeneration. It is inherited as autosomal recessive trait (STGD1), although STGD3 and STGD4 are inherited as autosomal dominant inheritance pattern. STGD3 is caused by mutations in the elongation of very long-chain fatty acids-like 4 (ELOVL4) gene encoding for a very long-chain fatty acid elongase. Mutations lead to a truncated Elovl4, lacking of a dilysine motif necessary for retention of transmembrane proteins in the endoplasmic reticulum...

Stargardt disease-4 (STGD4) is an autosomal dominant complex, genetically heterogeneous macular degeneration/dystrophy (MD) disorder. In this paper, we used targeted next generation sequencing and multiple molecular dynamics analyses to identify and characterize a disease-causing genetic variant in four generations of a Chinese family with STGD4-like MD. We found a novel heterozygous missense mutation, c.734T>C (p.L245P) in the PROM1 gene. Structurally, this mutation most likely impairs PROM1 protein stability, flexibility, and amino acid interaction network after changing the amino acid residue Leucine into Proline in the basic helix-loop-helix leucine zipper domain...

BACKGROUND: CLN3 disease is a major cause of childhood neurodegeneration. Onset of visual failure around 6 years of age is thought to precede cognitive deterioration by a few years, but casuistic reports question this paradigm. The aim of our study is to delineate timing of cognitive decline in CLN3 disease. METHODS: Early neurocognitive functioning in CLN3 disease was analyzed using age at onset of visual and cognitive decline and IQ scores from literature-derived patient descriptions, supplemented with IQ scores and school history from a retrospective referral center cohort...

Purpose: To assess retinal function in combination with the retinal structure in ABCA4-associated retinal degenerations. Moreover, to evaluate the possibility of predicting the natural course of these disorders. Methods: 34 patients with Stargardt disease or cone rod dystrophy carrying confirmed mutations in ABCA4 were selected from our retinitis pigmentosa (RP) register. Sequence analysis of the entire coding region of the ABCA4 gene was performed. The patients were subdivided into three groups based on their most recent visual fields...

BACKGROUND: Earlier studies have raised the notion that docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplementation could be a useful intervention in autosomal dominant Stargardt macular dystrophy (STGD3). We sought to assess whether fish oil supplementation has a beneficial effect on the clinical course of STGD3 secondary to a mutation in the ELOVL4 gene. MATERIALS AND METHODS: Eleven patients with STGD3 were enrolled in an 8-year open-label, clinical interventional study of over-the-counter fish oil supplements at a recommended daily dose of 650 mg EPA and 350 mg DHA (NCT00420602)...

Accumulation of lipofuscin in the retinal pigmented epithelium (RPE) is observed in retinal degenerative diseases including Stargardt disease and age-related macular degeneration. Bis-retinoid N-retinyl-N-retinylidene ethanolamine (A2E) is a major component of lipofuscin. A2E has been implicated in RPE atrophy and retinal inflammation; however, mice with A2E accumulation display only a mild retinal phenotype. In the current study, human iPSC-RPE (hiPSC-RPE) cells were generated from healthy individuals to examine effects of A2E in human RPE cells...

PURPOSE: Choroidal thickness (CT) evaluation with EDI-OCT in Stargardt Disease (STGD), considering its possible association with some clinical features of the disease. METHODS: CT was evaluated in 41 STGD patients and in 70 controls. Measurements were performed in the subfoveal position and at 1000 μm nasally and temporally. CT average values in STGD and in the control group were first compared by means of Student's T test. Then, the possible association between CT and some clinical features was evaluated by means of linear regression analysis...

PURPOSE: To investigate the prevalence of peripheral pigmented retinal lesions and associated clinical findings in patients with Stargardt disease. DESIGN: Retrospective case series. METHODS: Records at a single academic institution were reviewed for patients with genetically confirmed Stargardt disease with peripheral pigmented retinal lesions on wide-field retinal imaging. For this cohort we described demographics, clinical features, and pathogenic variants...

PURPOSE: To describe co-occurrence of choroidal osteoma in a patient with pattern dystrophy of retinal pigment epithelium. METHODS: Clinical case report RESULTS: A young female presented with decreased vision in the right eye due to decalcification of choroidal osteoma. Multimodal imaging including fundus autofluorescence, fluorescein angiography and optical coherence tomography showed features of pattern dystrophy of retinal pigment epithelium that simulates the Stargardt disease...

The advent of gene editing has introduced the ability to make changes to the genome of cells, thus allowing for correction of genetic mutations in patients with monogenic diseases. Retinal diseases are particularly suitable for the application of this new technology because many retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA), are monogenic. Moreover, gene delivery techniques such as the use of adeno-associated virus (AAV) vectors have been optimized for intraocular use, and phase III trials are well underway to treat LCA, a severe form of inherited retinal degeneration, with gene therapy...

Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4-/- Stargardt model mice compared to their relevant background strain...

The retinal pigment epithelium (RPE) interacts closely with photoreceptors to maintain visual function. In degenerative diseases such as Stargardt disease and age-related macular degeneration, the leading cause of blindness in the developed world, RPE cell loss is followed by photoreceptor cell death. RPE cells can proliferate under certain conditions, suggesting an intrinsic regenerative potential, but so far this has not been utilised therapeutically. Here, we used E2F2 to induce RPE cell replication and thereby regeneration...

Stargardt disease (STGD1), due to mutations in the large ABCA4 gene, is the most common inherited macular degeneration in humans. Attempts at developing gene therapy approaches for treatment of STGD1 are currently ongoing. Among all the vectors available for gene therapy of inherited retinal diseases, those based on adeno-associated viruses (AAV) are the most promising given the efficacy shown in various animal models and their excellent safety profile in humans, as confirmed in many ongoing clinical trials...